Previously we have discussed the design of organic molecules that mimic the catalytic activity of the serine transacylase enzymes. We are now in a position consider many of the 30 reactions involved in the synthesis compound 2, a serine transacylase mimic that contains three of the four structural elements required for catalytic activity; a serine hydroxyl group, a histidine imidazole, and a complexing site.
Before we consider the nucleophilic substitution reactions involved in the synthesis of 2, we'll take a brief look at the evolution of host-guest chemistry. We'll start with some relatively simple compounds called crown ethers.
In 1967 C.J. Pedersen, a DuPont chemist, reported the results of a study of the chemistry of a group of cyclic polyethers that have since come to be called crown ethers. One of the simplest of these compounds is contains an 18-membered ring in which 6 of the atoms are oxygens. It is called 18-crown-6. This compound forms complexes with metal ions as shown below. Clearly this is a simple example of host-guest interactions; the crown ether contains a cavity into which a metal ion such as a potassium ion fits snugly.
The synthesis of 18-crown-6 is summarized in Figure 1.
A Simple Synthesis Involving an Sn2 Reaction
In this reaction the KOH acts as a base to deprotonate the HO groups of the diols, creating nucleophilic oxygen atoms that displace the chlorine atoms from the primary carbons of the 1,2-dichloroethanes. When the crown ether is formed, it complexes the potassium ions that are present in the solution.
The next level of sophistication of host-guest interactions involves compounds called cryptands, a simple example of which is shown below:
The presence of the trivalent nitrogen atoms adds a 3-dimensional quality to cryptands that is missing in simple crown ethers. Where a crown ether may be thought of as a plate on which a metal ion sits, a cryptand is more like a cup into which you may put metal ions or other small molecules. The 3-dimensional nature of crytpands is an essential structural feature of enzymes. The cup-like nature of these molecules is found in the complexation sites of enzymes and of enzyme mimics such as compound 2. In Figure 2 the cryptand shown above is deconstructed into the components from which it was made. All of the steps required for the synthesis of this compound involve Sn2 reactions.
Deconstructing a Cryptand
Now let's turn our attention to the preparation of compound 2. The discussion that follows focuses on those steps of the synthesis of 2 that involve nucleophilic aliphatic substitution reactions. To clarify the logic that underlies this synthesis, we will start at the target and work backwards towards the starting materials. The synthesis of 2 was described in an article entitled Synthesis and Binding Properties of a Tranacylase Partial Mimic with Imidazole and Benzyl Alcohol in Place in the journal Tetrahedron Symposium In Print 42, 1607-1615, 1986.
Nucleophilic Aliphatic Substitution Reactions in Organic Synthesis
Figure 3 summarizes the final stages of the preparation of compound 2. The key step involves a double nucleophilic aliphatic substitution reaction of the bis-amide 8 with the bis-benzyl bromide 9 to form 10 which contains a 20-membered ring that comprises the complexing site of the target.
Circle the Wagons
Sodium hydride, NaH, is a strong base that deprotonates the amide nitrogens in 8. The negatively charged nitrogen atoms in the resulting dianion displace the bromine atoms from the benzylic carbons in 9 to produce 10 in 68% yield. The last step in the synthesis involves acid catalysed hydrolysis of the protecting group for the alcohol function in 2. Scheme 1 presents a mechanistic interpretation of this reaction.
Deprotection of an Alcohol
Protonation of the oxygen atom in 10 generates an oxonium ion intermediate which ionizes to produce 2 and a carbocation that reacts with water to form methanol and formaldehyde. This
Figure 4 outlines the preparation of compound 9.
Deprotection of an Alcohol II
Scheme 2 highlights the essential feature of the sequence of reactions outlined in Figure 4, namely the conversion of 14 to 15 by nucleophilic substitution at silicon. The tetrabutyl ammonium fluoride, Bu4NF, is a source of fluoride ion, which acts as a nucleophile toward the silicon atoms in 14.
A Mechanism for Deprotection
Figure 5 summarizes several steps in the preparation of compound 13. The formation of compound 25 involves nucleophilic substitution by hydroxide ion on the primary alkyl bromide that was produced by bromination of compound 24. Hydrolysis of 25 produced 26, which acted as a triple nucleopnile in its reaction with CH3OCH2Br to produce an intemediate structure which was reduced with lithium aluminum hydride to generate compound 27. Protection of the hydroxyl groups in 27 with t-butyldimethylchlorosilane yielded compound 13.